The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has approved Xolremdi (mavorixafor, X4 Pharmaceuticals GmbH) for the treatment of WHIM syndrome, an ultra-rare hereditary immunodeficiency disease.

WHIM stands for “warts, hypogammaglobulinemia, infections, and myelokathexis.” The syndrome is a long-term debilitating and life-threatening condition in which there is increased responsiveness to tumor promoters and retention of leukocytes in bone marrow. Patients are vulnerable to recurrent severe infections and have an increased risk for developing viral-associated cancer. There is currently no other licensed treatment option.

WHIM is due to gain-of-function mutations in the CXC chemokine receptor 4 gene (CXCR4). This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1 (CXCL12), which plays a pivotal role in tumor development, survival, angiogenesis, metastasis, and the tumor microenvironment.

Bone Marrow Leukocytes Released 

Mavorixafor is an immunostimulant: a CXCR4 antagonist that binds to the CXCR4 receptor, preventing its interaction with CXCL12. By inhibiting this interaction, mavorixafor increases mobilization of neutrophils, lymphocytes, and monocytes from the bone marrow into the peripheral circulation.

The CHMP recommended exceptional use authorization for mavorixafor in patients aged 12 years or older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. This type of authorization may be granted when an applicant is unable to provide comprehensive data on the efficacy and safety of the medicinal product due to the rarity of the condition it is intended for, limited scientific knowledge in the area concerned, or ethical considerations involved in the collection of such data. Authorization is subject to certain specific obligations, to be reviewed annually.

Trial Evidence

The CHMP said that a randomized, double-blind, placebo-controlled study in 31 patients with WHIM syndrome showed that mavorixafor increased the number of circulating mature neutrophils and lymphocytes. This had some effect in reducing infections, although an effect on warts was not shown, nor was a preventive effect on malignancies.

The most common side effects with mavorixafor are gastrointestinal (nausea, diarrhea, vomiting, dyspepsia and abdominal pain), rash, and headache. 

The drug is available as 100-mg hard capsules. Treatment should be initiated only by specialist physicians with experience in the diagnosis or management of immune deficiencies.

Mavorixafor was designated as an orphan medicine in 2019. These are drugs developed for use against rare, life-threatening, or chronically debilitating conditions that, for economic reasons, would be unlikely to be developed without incentives. The EMA will now review the information available to date to determine if the orphan designation can be maintained.

Commercialization in Europe is a result of a partnership between X4 Pharmaceuticals and Norgine B.V., a European specialty pharmaceutical company. It said the CHMP recommendation marked a major step toward a first authorized treatment for WHIM syndrome in Europe. 

Detailed recommendations for the use of this product will be described in the Summary of Product Characteristics, which will be published on the EMA website in all official European Union languages after the marketing authorization has been granted by the European Commission.

Dr Sheena Meredith is an established medical writer, editor, and consultant in healthcare communications, with extensive experience writing for medical professionals and the general public. She is qualified in medicine and in law and medical ethics.